DNA Destruction Through Novel and Adaptable Enzymes

Bacteria in mixed populations compete for resources and have several strategies on surviving and dominating other bacterial species. One method employs the injection of lethal effectors into adjacent cells. These effectors can disrupt cell membranes and degrade proteins or nucleic acids. Bacteria within the same population survive by neutralizing effectors while the other population is destroyed. This is an important mechanism in the gut microbiome where there is a mixed community of bacteria and potential for pathogenic bacteria to overtake commensal bacteria, while low abundance bacteria are able to survive through an indeterminate mechanism. Degradation of DNA is a powerful way to target diseases that include exogenous DNA as part of their disease pathology. For example, Pulmozyme®, which utilizes a human deoxyribonuclease I (DNase I), was clinically approved in 1993 for therapeutic use in cystic fibrosis. It has also been investigated for other pulmonary diseases and as a combination with antibiotics against biofilms. However, DNaseI is a large protein (~37kDa), can bind with other proteins (which reduces efficacy), and is costly and difficult to produce. Novel DNA-degrading enzymes could provide therapeutics for inflammatory diseases, respiratory diseases, and cancer.

Technology: Dr. Gibb’s lab discovered new DNA-degrading enzymes engineered from Proteus mirabilis (D) and Rothia aeria (R) and are now able to design and produce functional derivatives of these two enzymes. The group demonstrated modularity in function and flexibility in amino acid sequences through a combination of biochemical assays and metagenomics methods. Both R and D enzymes were ~16kDa and can be engineered, produced, and preserve functionality.

Advantages: The ability to engineer novel DNA degrading enzymes opens up a wide variety of clinical applications such as inhibiting tumor cell proliferation in cancer, autoimmune disorders, pulmonary diseases, and sepsis. Other potential applications could be in aquatic technologies including the disruption of biofouling and control of biofilms, and basic biology research tools.

Intellectual Property Status: Patent(s) Pending